MARVEL on protease mutations at position 54

HIVdb Algorithm: Comments & Scores

I54A/T/S are nonpolymorphic PI-selected mutations that occur almost exclusively in patients who have received multiple PIs. I54A/T/S are associated with reduced susceptibility to each of the PIs except DRV.

I54L is a nonpolymorphic mutation selected by FPV, LPV and DRV. It reduces susceptibility to these PIs and possibly to ATV, IDV, NFV and SQV. It increases susceptibility to TPV. It is in the Tibotec DRV GSS.

I54M is a nonpolymorphic mutation selected by FPV, LPV and DRV. It reduces susceptibility to each of the PIs. It is in the Tibotec DRV GSS.

I54V is a nonpolymorphic mutation selected primarily by IDV and LPV. It reduces susceptibility to each of the PIs except DRV. It synergistically reduces PI susceptibility when present in combination with V82 mutations.

Mutation

FPV/r

IDV/r

NFV

SQV/r

LPV/r

ATV/r

TPV/r

DRV/r

I54A

10

15

20

15

10

15

20

0

I54L

60

10

20

15

15

15

-10

20

I54M

60

15

20

15

15

15

20

20

I54S

10

15

20

15

10

15

20

0

I54T

10

15

20

15

10

15

20

0

I54V

10

15

20

15

15

15

20

0

Footnote:Mutation scores on the left are derived from published literature linking mutations and ARVs (the complete details can be found in the HIVdb Release Notes).

Genotype-treatment correlation

Mutation frequency according to subtype and drug-class experience.

The frequency of each mutation at position 54 according to subtype and drug-class experience. Data are shown for the 8 most common subtypes. The number of persons in each subtype/treatment category is shown beneath the subtype. Mutations occurring at a frequency >0.5% are shown. Each mutation is also a hyper-link to a separate web page with information on each isolate, including literature references with PubMed abstracts, the GenBank accession number, and complete sequence and treatment records.

The first row shows the frequency of the mutation in persons who are PI-naive (indicated in green). The second row shows the frequency of the mutation in persons who have received one or more PIs. The following rows show the frequency of the mutation in persons who have received only a single PI. Mutation rates that differ significantly between treated and untreated isolates are indicated in yellow.

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54A

0

64379

0

I54A

>=1

13892

166

1.10

0.000

I54A

APV

72

0

I54A

IDV

1177

6

0.50

0.000

I54A

LPV

1238

1

0.00

0.000

I54A

NFV

1175

1

0.00

0.000

I54A

SQV

458

0

I54A

ATV

220

0

I54A

TPV

0

0

I54A

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54F

0

64379

7

0.00

I54F

>=1

13892

4

0.00

0.222

I54F

APV

72

0

I54F

IDV

1177

0

I54F

LPV

1238

1

0.00

0.364

I54F

NFV

1175

0

I54F

SQV

458

0

I54F

ATV

220

1

0.40

0.004

I54F

TPV

0

0

I54F

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54L

0

64379

8

0.00

I54L

>=1

13892

418

3.00

0.000

I54L

APV

72

7

9.70

0.000

I54L

IDV

1177

1

0.00

0.395

I54L

LPV

1238

1

0.00

0.418

I54L

NFV

1175

5

0.40

0.000

I54L

SQV

458

2

0.40

0.000

I54L

ATV

220

1

0.40

0.007

I54L

TPV

0

0

I54L

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54M

0

64379

0

I54M

>=1

13892

370

2.60

0.000

I54M

APV

72

5

6.90

0.000

I54M

IDV

1177

0

I54M

LPV

1238

1

0.00

0.000

I54M

NFV

1175

0

I54M

SQV

458

1

0.20

0.000

I54M

ATV

220

0

I54M

TPV

0

0

I54M

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54S

0

64379

1

0.00

I54S

>=1

13892

92

0.60

0.000

I54S

APV

72

0

I54S

IDV

1177

0

I54S

LPV

1238

0

I54S

NFV

1175

0

I54S

SQV

458

0

I54S

ATV

220

0

I54S

TPV

0

0

I54S

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54T

0

64379

8

0.00

I54T

>=1

13892

115

0.80

0.000

I54T

APV

72

1

1.30

0.000

I54T

IDV

1177

4

0.30

0.000

I54T

LPV

1238

0

I54T

NFV

1175

0

I54T

SQV

458

1

0.20

0.082

I54T

ATV

220

0

I54T

TPV

0

0

I54T

DRV

8

0

Mutation

PI

NumSeq

NumMut

% Mutant

p

I54V

0

64379

3

0.00

I54V

>=1

13892

3618

26.00

0.000

I54V

APV

72

1

1.30

0.000

I54V

IDV

1177

186

15.80

0.000

I54V

LPV

1238

148

11.90

0.000

I54V

NFV

1175

30

2.50

0.000

I54V

SQV

458

49

10.60

0.000

I54V

ATV

220

2

0.90

0.000

I54V

TPV

0

0

I54V

DRV

8

0

Footnote: Data are not shown for TPV or DRV because there are no data available from persons who have developed virological failure after receiving just one of these PIs; About one-half of the untreated isolates belong to non-subtype B isolates; About 20% of the treated isolates belong to non-subtype B isolates; A page containing summaries for all of the mutations at this position can be found here.

Genotype-phenotype correlation

Phenotypes of top 10 common patterns of drug resistance mutations with mutations at position 54.

Mutation patterns are listed in the frequency with which they have been reported in the published literature. The median level of fold resistance (compared with wildtype) for viruses with the mutation pattern in the first column are indicated when available. The subscripts indicate the number of viruses that were phenotyped. The drug susceptibility assay used was the PhenoSense assay (Monogram, South San Francisco). A hyperlink for each individual pattern is provided to access a complete list of mutations and fold resistances for each sequence matching the pattern of mutation.

A complete summary of additional in vitro susceptibility data for viruses with I54 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with I54 (not just the top 10 most frequent patterns) can be found at this page.

Footnote: Mutation patterns were defined by the presence or absence of major PI drug resistance mutations ; Sequences containing a mixture at a major drug resistance positions were excluded; For the cutoffs defined by PhenoSense, open the sample report form provided on this page; The full list of all mutation patterns are also available here.

Phenotypic coefficients using machine learning

Least Square Regression (LSR) was used to learn the relative contribution of each mutation to the fold decrease in susceptibility for an ARV. The figure on the left (click to enlarge the figure) shows the regression coefficients (which correlate with the contribution to resistance) for the 35 nonpolymorphic PI-resistance mutations shown to contribute decreased susceptibility to at least one PI. A complete description of the method that generates this figure can be found at Rhee et al PNAS 2006.

Genotype-clinical outcome correlation

Studies correlating baseline genotype and virological response to an ARV therapy with or without mutations at 54.

L10F/I/V, K20M/R, L24I, M46I/L, Q58E, L63P, G73S/A, V77I, V82A/F/S/T, I84A/V, L90M were associated with failure to reach RNA <50 copies/ml (p<=0.1) in a univariate analysis. A score that also included I54L/M/T/V, A71I/L/V/T was significantly associated with response in that 63% of persons with <5 total mutations vs 11% with >=5 total mutations had RNA <50 copies/ml. G16E and D60E occurred at baseline in 5 and 9 persons, respectively, but were not associated with VR.

13 PI mutations at baseline were associated with a reduced VR: 10F/I/V, 16E, 33F/I/V, 46I/L, 60E, 84V, 85V, and 90M. RNA decrease >1 log occurred in 100% with <2 mutations, 80% with 2 mutations, 43% with 3 mutations, and 0% with 4-5 mutations. In a follow-up study of 53 patients (Marcelin 2006), only four mutations (L10F/I/V, L33F/I, I84V, and L90M were predictive of reduced response, although the original score remained predictive.

V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V at baseline were associated with a decreased VR to DRV/r. About 60% with 0, 45% with 1-2, and <=20% with >=3 DRMs had RNA <50 copies/ml at wk 24. In phenotypic studies, I50V, I54M, L76V, and I84V reduced susceptibility to the greatest extent. V32I emerged in 30% of failures according to prescribing information.

Ten of the 11 mutations (all except G73S: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V) in the previous De Meyer 2008 study and a new mutation T74P were associated with a decreased VR (defined by RNA <50 copies/ml) at W24. In patients who did not received T20, harboring >=3 of these mutations were associated a decreased VR.

26(40%) of patients resulted in VF which was defined as RNA >2.3 at W12. I13V, V32I, L33F/I/V, E35D, M36I/L/V, I47V, F53L,I62V at baseline were associated with increased VF. Adjusted OR for resulting in a VF for one addition of these mutations was 6.2. 11% with <4 , 48% with 4-5 and 100% with >5 these mutations resulted in a VF.

The mutations I15V + M46IL + I54LMV + D60E + L63PT + I84V. Persons with 0 or 1 mutation had a mean 2 log decrease, those with 2 mutations had a median 1.5 log decrease, and those with >=3 mutations had <=0.6 log decreases. Mutations at positions 10, 33, 73, and 90 were negatively associated with response in univariate analyses. In this APV/FPV-naive population, no patient had V32I, I47V, or I50V.

The Genotypic Inhibitory Quotient (GIQ) defined as the median LPV Cmin concentration divided by the number of mutations at the following positions (10, 20, 24, 33, 36, 47, 48, 54, 82, 84). In a multivariate analysis, the GIQ but not the number of mutations was significantly associated with VR.

21 mutations at 16 positions were found to correlate with a decreased VR to TPV/r salvage therapy: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. Each additional mutation was associated with a 0.04 log decreased 2-week and 0.16 log decreased 24 week response. The 24 week response dropped from 1.3 logs when 3 mutations were present to 0.64 logs when 4 mutations were present and was completely lost when 8 mutations were present. Note: The vast majority of isolates used to derive the list belonged to subtype B which is relevant because I13V, K20 mutations, M36I, and H69K are highly common in several non-B subtypes.

79 (55%) patients achieved VR defined by a decrease of >= 1 log or a BLQ in RNA level at week 12. Baseline mutations at 6 positions found to be associated with a lower VR and one with a higher VR were used for GSS: E35D/G/K/N + M36I/L/V - F53L/W/Y + Q58E + Q61D/E/G/H/N/R + H69I/K/N/Q/R/Y + L89I/M/R/T/V. 100% patients with a GSS of -1, 79% with 0, 56% with 1, 33% with 2, 21% with 3 and 0% with 4 achieved VR.